title: Inactivating mutations of acetyltransferase genes in B-cell lymphoma.
abstract: B-cell non-Hodgkin's lymphoma comprises biologically and clinically distinct diseases the pathogenesis of which is associated with genetic lesions affecting oncogenes and tumour-suppressor genes. We report here that the two most common types--follicular lymphoma and diffuse large B-cell lymphoma--harbour frequent structural alterations inactivating CREBBP and, more rarely, EP300, two highly related histone and non-histone acetyltransferases (HATs) that act as transcriptional co-activators in multiple signalling pathways. Overall, about 39% of diffuse large B-cell lymphoma and 41% of follicular lymphoma cases display genomic deletions and/or somatic mutations that remove or inactivate the HAT coding domain of these two genes. These lesions usually affect one allele, suggesting that reduction in HAT dosage is important for lymphomagenesis. We demonstrate specific defects in acetylation-mediated inactivation of the BCL6 oncoprotein and activation of the p53 tumour suppressor. These results identify CREBBP/EP300 mutations as a major pathogenetic mechanism shared by common forms of B-cell non-Hodgkin's lymphoma, with direct implications for the use of drugs targeting acetylation/deacetylation mechanisms.
authors.affiliation: Institute for Cancer Genetics, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York 10032, USA. lp171@columbia.edu
authors.forename: Laura
authors.initials: L
authors.lastname: Pasqualucci
authors.forename: David
authors.initials: D
authors.lastname: Dominguez-Sola
authors.forename: Annalisa
authors.initials: A
authors.lastname: Chiarenza
authors.forename: Giulia
authors.initials: G
authors.lastname: Fabbri
authors.forename: Adina
authors.initials: A
authors.lastname: Grunn
authors.forename: Vladimir
authors.initials: V
authors.lastname: Trifonov
authors.forename: Lawryn H
authors.initials: LH
authors.lastname: Kasper
authors.forename: Stephanie
authors.initials: S
authors.lastname: Lerach
authors.forename: Hongyan
authors.initials: H
authors.lastname: Tang
authors.forename: Jing
authors.initials: J
authors.lastname: Ma
authors.forename: Davide
authors.initials: D
authors.lastname: Rossi
authors.forename: Amy
authors.initials: A
authors.lastname: Chadburn
authors.forename: Vundavalli V
authors.initials: VV
authors.lastname: Murty
authors.forename: Charles G
authors.initials: CG
authors.lastname: Mullighan
authors.forename: Gianluca
authors.initials: G
authors.lastname: Gaidano
authors.forename: Raul
authors.initials: R
authors.lastname: Rabadan
authors.forename: Paul K
authors.initials: PK
authors.lastname: Brindle
authors.forename: Riccardo
authors.initials: R
authors.lastname: Dalla-Favera
mesh_terms: D000105:Acetyl Coenzyme A / Q000378:metabolism; D000107:Acetylation; D000123:Acetyltransferases / Q000737:chemistry / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D050882:CREB-Binding Protein / Q000737:chemistry / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D050881:E1A-Associated p300 Protein / Q000737:chemistry / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D051548:Histone Acetyltransferases / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016393:Lymphoma, B-Cell / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D008224:Lymphoma, Follicular / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D051379:Mice; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011485:Protein Binding; D017434:Protein Structure, Tertiary / Q000235:genetics; D051560:Proto-Oncogene Proteins c-bcl-6; D012008:Recurrence; D017384:Sequence Deletion / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C084103:BCL6 protein, human; D004268:DNA-Binding Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D016159:Tumor Suppressor Protein p53; D000105:Acetyl Coenzyme A; D000123:Acetyltransferases; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; D051548:Histone Acetyltransferases